FDA Grants Orphan Drug Designation to FORE8394 for Primary Brain and CNS Malignancies

Stacie Shepherd, MD, PhD

The FDA has granted an orphan drug designation to FORE8394 for the treatment of primary brain and central nervous system (CNS) malignancies, according to an announcement from Fore Biotherapeutics.¹

FORE8394 is an investigational, novel, small-molecule, next-generation, oral, selective BRAF inhibitor that is designed to target a range of BRAF mutations and spare RAF wild-type.

“The receipt of orphan drug designation is another important regulatory achievement that reinforces the FDA’s recognition of the potential of FORE8394 to improve clinical outcomes in patients with BRAF-altered brain tumors,” Stacie Shepherd, MD, PhD, chief medical officer of Fore Biotherapeutics, stated in a news release. “This designation will help us continue to expedite the development of our novel BRAF inhibitor, and we look forward to working closely with the global investigator community supporting [the phase 2] FORTE [trial (NCT05503797)] and to advancing the development of FORE8394 for patients in need.”

Previous data from preclinical studies and clinical trials have shown that the unique mechanism of action of FORE8394 effectively inhibits BRAF V600 monomers targeted by first-generation RAF inhibitors and disrupts constitutively active dimeric BRAF class 2 mutants, fusions, splice variants, and others. Additionally, unlike first-generation RAF inhibitors, FORE8394 does not induce paradoxical activation of the RAF/MEK/ERK pathway.

The agent is under investigation in the phase 2 FORTE trial in patients with locally advanced or metastatic solid tumors, or recurrent or progressive primary CNS tumors harboring BRAF fusions (group A), and in patients with recurrent BRAF V600E–mutated high-grade glioma (group B).²

Patients in group A are required to be at least 10 years of age and weigh at least 30 kg with a histologic diagnosis of a solid tumor or primary CNS tumor with a BRAF mutation. Patients need to have received at least available standard therapy, be intolerant to available therapies, or have an investigator determine that treatment with standard therapy is not appropriate.

Key exclusion criteria in group A include co-occurring NF1 alterations and/or RAS-related mutations, prior treatment with RAF/BRAF inhibitors active for class 2 BRAF alterations for advanced unresectable or metastatic disease, or prior treatment with a MEK inhibitor. Prior treatment with TKIs, targeted therapies, chemotherapy, and/or immunotherapy is allowed.

In group B, patients must be at least 10 years of age and weigh at least 30 kg with a histological diagnosis of a grade 3 or 4 glioma or glioneuronal tumor harboring a BRAF V600E mutation. Patients must have received at least 1 line of prior therapy including radiation, although those for whom radiotherapy is not considered standard of care can be eligible for the trial.

Key exclusion criteria for group B include prior treatment with BRAF, ERK, and/or MEK inhibitors, known or suspected NF1 and/or RAS-related gene alterations, or active infection requiring systemic therapy.

Enrolled patients in both groups will receive 900 mg of oral FORE8394 with 150 mg of cobicistat once per day in continuous 3-week cycles until disease progression, unacceptable toxicity, or other reason for withdrawal.

Objective response rate (ORR) per blinded independent central review is serving as the trial’s primary end point. Secondary end points include duration of response (DOR), investigator-assessed ORR, CNS DOR in group A, time to response, progression-free survival, overall survival, CNS ORR in group A, and safety.

“Available treatments are limited for patients with primary recurrent CNS tumors or those patients living with solid tumors with a BRAF fusion,” Matthew Ros, chief executive officer of Fore Biotherapeutics, stated in a news release.¹ “With its unique mechanism of action as a paradox breaker, we believe we have a significant opportunity to deliver a novel and best in class potential therapeutic option with FORE8394. We look forward to accelerating enrollment in the phase 2 Forte master protocol throughout 2023.”

References

1. FORE Biotherapeutics receives FDA orphan drug designation for FORE8394 for the treatment of primary brain and CNS malignancies. News release. FORE Biotherapeutics. March 20, 2023. Accessed March 21, 2023. https://fore.bio/fore-biotherapeutics-receives-fda-orphan-drug-designation
2. A study to assess the efficacy and safety of FORE8394 in participants with cancer harboring BRAF alterations. ClinicalTrials.gov. Updated March 15, 2023. Accessed March 21, 2023. https://www.clinicaltrials.gov/ct2/show/NCT05503797